Researchers from the MRC Lifecourse Epidemiology Unit and the Institute of Developmental Sciences at the University of Southampton, as part of the Epigen Global Consortium, looked at whether bone health might be influenced by epigenetic modifications of DNA early in life.
The results, published in the Journal of Bone and Mineral Research, provide an insight into the early determinants of skeletal growth, and improve the understanding of how osteoporosis could be prevented in future generations.
There is growing evidence that whether genes are expressed or not (switched on or off) in particular human cells can change throughout life and can be affected by a range of environmental factors even before birth, such as their parents' health, diet and lifestyle before and during pregnancy. This switching on or off of genes is known as "epigenetic modification" and an important epigenetic mechanism is DNA methylation.
The Southampton researchers analysed the levels of DNA methylation in umbilical cord tissue of 669 babies born in the Southampton Women's Survey.
They compared the DNA methylation levels in the CDKN2A gene to the bone mass of the child at four and six years of age, measured using DXA bone densitometry. They found that higher DNA methylation in particular parts of the CDKN2A gene, which is known to play a role in development and ageing, was associated with lower bone mass at four and six years.
Analysis showed that a 10 percent increase in methylation was associated with a decrease in total bone mass of around 4-9g at age four years. Further laboratory analysis showed that methylation of the CDKN2A region is important for the function and survival of bone cells.
Nicholas Harvey, Professor of Rheumatology and Clinical Epidemiology at the University of Southampton, led the study with Dr Elizabeth Curtis, Wellcome Trust Clinical Research Fellow, and Dr Robert Murray, Postdoctoral Research Fellow, both also from the University.
He said: "The health of a child's bone when they are young can influence the risk of osteoporosis in older age. This study provides exciting insights into the role of epigenetics in bone health, and might allow us to more accurately predict an individual's future risk of osteoporosis. Our ongoing studies should enable us to work out whether interventions during pregnancy, for example vitamin D supplementation, will actually alter the epigenetic marks, and lead to improved bone health in the offspring."
Professor Cyrus Cooper, Director of the MRC Lifecourse Epidemiology Unit, said: "This major finding links our previous observations on maternal nutrition and lifestyle during pregnancy, with the later risk of musculoskeletal ageing in the offspring. It bears testimony to the value of large, well-maintained population cohorts, participants among whom are followed up for many years."
The EpiGen Global Consortium brings together expertise from the Human Development and Health Academic Unit, MRC Lifecourse Epidemiology Unit and Centre for Biological Sciences, University of Southampton; Singapore Institute for Clinical Sciences; National University of Singapore; Auckland UniServices Limited and the Liggins Institute, University of Auckland. The Consortium's aim is to improve human health through the life course by further understanding developmental and environmental processes. The research includes a focus on epigenetics, the biology of understanding how gene function is regulated by environmental factors, such as maternal nutrition, during the very early stages of development. This research was carried out as part of a collaboration with the Nestlé Research Centre, in Lausanne, Switzerland.

These changes, known as epigenetic modifications, control the activity of our genes without changing the actual DNA sequence. One of the main epigenetic modifications is DNA methylation, which plays a key role in embryonic development and the formation of different cell types, regulating when and where genes are switched on.
Although DNA methylation was originally thought to be a very stable modification, which once established in early life was then maintained throughout the life span of an individual, there is now growing evidence that the level of DNA methylation can be affected by a range of environmental factors such as parental health, diet and lifestyle.
Researchers from the University of Southampton, as part of the EpiGen Global Consortium, analysed the levels of DNA methylation, in umbilical cord tissue of babies born in the Southampton Women's Survey.
They compared DNA methylation levels present at birth with the amount of fat tissue in the child at four and six years of age. They found that lower DNA methylation at the CDKN2A gene, which regulates the production of fat cells, was associated with a greater risk of the child developing obesity in later life.
Analysis showed that a 10 percent decrease in methylation at the CDKN2A gene was associated with an increase in fat mass of around 220g, at age 4 years.
The results, published in EBio Medicine, were replicated in other groups of children and adults, notably the Singapore GUSTO study, the Australian RAINE study and the UK BIOCLAIMS cohort.
Lead author Karen Lillycrop said: "This is exciting new evidence that epigenetic changes detectable at birth are linked to a child's health as they grow up. It was very promising to see our initial findings confirmed in so many other cohorts. Not only does it strengthen the body of evidence that shows a mothers health during pregnancy can affect the future health of her child, but it could also allow us to more accurately predict the future risk of obesity. If we can do this, then preventative strategies can be developed in early life to prevent the development of obesity."
Professor Keith Godfrey, from the Medical Research Council Lifecourse Epidemiology Unit and the National Institute for Health Research Southampton Biomedical Research Centre and a member of the study team said: "The new findings provide the first direct evidence linking faltering of a baby's growth in the womb with epigenetic modifications that themselves may increase the risk of childhood obesity. The findings are now helping us to trial new nutritional interventions before and during pregnancy to reduce the baby's risk on obesity in childhood and later life, and strengthen the view that effective prevention of childhood obesity has to begin before the baby is born. The new findings may also lead to innovative approaches to the treatment of established obesity in later life."
The EpiGen Global Consortium brings together expertise from the Human Development and Health Academic Unit, MRC Lifecourse Epidemiology Unit and Centre for Biological Sciences, University of Southampton; Singapore Institute for Clinical Sciences; National University of Singapore; Auckland UniServices Limited and the Liggins Institute, University of Auckland. The Consortium's aim is to improve human health through the life course by further understanding developmental and environmental processes. The research includes a focus on epigenetics, the biology of understanding how gene function is regulated by environmental factors, such as maternal nutrition, during the very early stages of development. This research was carried out as part of a collaboration with the Nestlé Research Centre, in Lausanne, Switzerland.

Washington, DC -- Individualized supplement doses help protect pregnant women from vitamin D deficiency, according to a new study published in the Endocrine Society's Journal of Clinical Endocrinology & Metabolism.
The research found vitamin D supplements are less effective at raising vitamin D levels in pregnant women if they deliver their babies in the winter, have low levels of vitamin D early in pregnancy or gain more weight during pregnancy. Women with these risk factors may need higher doses during pregnancy than other mothers-to-be.
Vitamin D is a hormone that helps the body absorb calcium. It plays a crucial role in bone and muscle health. The skin naturally produces vitamin D after exposure to sunlight. People also obtain smaller amounts of the vitamin through foods, such as milk fortified with vitamin D.
Vitamin D deficiency is common, including among pregnant women. Evidence suggests vitamin D deficiency during pregnancy can harm maternal health, fetal development and the child's long-term skeletal health.
"It is critical for pregnant women to have sufficient levels of vitamin D for the health of their baby," said one of the study's authors, Nicholas C. Harvey, MA, MB, BChir, MRCP, PhD, Professor of Rheumatology and Clinical Epidemiology at the University of Southampton in Southampton, U.K. "Our study findings suggest that in order to optimize vitamin D concentrations through pregnancy, the supplemental dose given may need to be tailored to a woman's individual circumstances, such as the anticipated season of delivery."
The analysis examined data from the Maternal Vitamin D Osteoporosis Study (MAVIDOS), a multi-center, double-blind, randomized, placebo-controlled trial of vitamin D supplementation in pregnancy. The study examined vitamin D levels in 829 pregnant women who received early pregnancy ultrasounds at one of three United Kingdom hospitals.
Beginning around 14 weeks' gestation, the women were randomized to receive either a 1000 IU/day dose of a vitamin D3 supplement called cholecalciferol or a placebo. Researchers measured vitamin D levels in the participants' blood prior to the start of the study and again at 34 weeks' gestation.
Participants who received the supplement had varying levels of vitamin D in the blood, even though they received the same dose. Researchers found women who delivered in the summer, who gained less weight during pregnancy and who had higher vitamin D levels early in pregnancy tended to have higher levels of vitamin D in the blood than their counterparts. Women who consistently took the supplement also had higher levels of vitamin D than participants who did not.
"Our findings of varied responses to vitamin D supplementation according to individual attributes can be used to tailor approaches to prenatal care," said one of the study's authors, Cyrus Cooper, OBE, MA, DM, FRCP, FFPH, FMedSci, Professor of Rheumatology and Clinical Epidemiology at the University of Southampton's MRC Lifecourse Epidemiology Unit. "This work will inform the development of strategies to enhance bone development across generations."
The study, "Determinants of the Maternal 25-hydroxyvitamin D Response to Vitamin D Supplementation During Pregnancy," will be published online at http://press. , ahead of print.
Other authors of the study include: Rebecca J. Moon, Stefania D'Angelo, Sarah R. Crozier, Hazel M. Inskip, Elaine M. Dennison and Sian M. Robinson of Southampton General Hospital in Southampton, U.K.; Inez Schoenmakers and Ann Prentice of the Elsie Widdowson Laboratory in Cambridge, U.K.; Nigel K. Arden, Andrew Carr and M. Kassim Javaid of the University of Oxford in Oxford, U.K.; Nicholas J. Bishop of Sheffield Children's Hospital and the University of Sheffield in Sheffield, U.K.; Richard Eastell of the University of Sheffield in Sheffield, U.K.; Robert Fraser and Saurabh V. Gandhi of the Sheffield Hospitals NHS Trust in Sheffield, U.K.; Keith M. Godfrey of Southampton General Hospital and the University of Southampton in Southampton, U.K.; Stephen Kennedy and Aris T. Papageorghiou of John Radcliffe Hospital at the University of Oxford in Oxford, U.K.; M. Zulf Mughal of Royal Manchester Children's Hospitals in Manchester, U.K.; and David M. Reid at the University of Aberdeen in Aberdeen, U.K.
The research was supported by grants from Arthritis Research UK, Medical Research Council, Bupa Foundation, National Institute for Health Research (NIHR) Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, and NIHR Musculoskeletal Biomedical Research Unit, University of Oxford. Merck GmbH provided the vitamin D supplement used in the study.
For more information on vitamin D, visit the Hormone Health Network's website.
Endocrinologists are at the core of solving the most pressing health problems of our time, from diabetes and obesity to infertility, bone health, and hormone-related cancers. The Endocrine Society is the world's oldest and largest organization of scientists devoted to hormone research and physicians who care for people with hormone-related conditions.
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Vitamin D supplements are less effective at raising vitamin D levels in pregnant women if they deliver their babies in the winter, have low levels of vitamin D early in pregnancy or gain more weight during pregnancy, a new Southampton study has shown.
The findings, published the Endocrine Society's Journal of Clinical Endocrinology & Metabolism, showed pregnant women respond differently to vitamin D supplementation depending on their individual attributes.
The University of Southampton researchers suggest that supplement levels should be tailored according to individual risk factors.
Vitamin D is a hormone that helps the body absorb calcium. It plays a crucial role in bone and muscle health. The skin naturally produces vitamin D after exposure to sunlight but people also obtain smaller amounts of the vitamin through foods, such as milk fortified with vitamin D.
Evidence suggests vitamin D deficiency during pregnancy can harm maternal health, fetal development and the child's long-term skeletal health.
Professor Nicholas Harvey, of the Medical Research Council Lifecourse Epidemiology Unit, University of Southampton, who led the study with Dr Rebecca Moon, Clinical Research Fellow, comments: "It is important for pregnant women to have sufficient levels of vitamin D for the health of their baby. Our study findings suggest that in order to optimise vitamin D concentrations through pregnancy, the supplemental dose given may need to be tailored to a woman's individual circumstances, such as the anticipated season of delivery."
The Maternal Vitamin D Osteoporosis Study (MAVIDOS), is a multi-centre, double-blind, randomised, placebo-controlled trial of vitamin D supplementation in pregnancy. More than 800 pregnant women were recruited and randomised to take either 1000 units (25 micrograms) of vitamin D every day or a matched placebo capsule from 14 week's gestation until delivery of the baby.
Analysis showed that participants who received the vitamin D supplement achieved different levels of vitamin D in the blood, even though they received the same dose. Researchers found women who delivered in the summer, who gained less weight during pregnancy and who had higher vitamin D levels early in pregnancy tended to have higher levels of vitamin D in the blood than their counterparts. Women who consistently took the supplement also had higher levels of vitamin D than participants who did not.
"Our findings of varied responses to vitamin D supplementation according to individual attributes can be used to tailor approaches to antenatal care," said Professor Cyrus Cooper, Director, and Professor of Rheumatology at the MRC Lifecourse Epidemiology Unit, University of Southampton. "This work forms part of a larger programme of research at the MRC Lifecourse Epidemiology Unit, University of Southampton, addressing the early life determinants of bone development, and will inform novel strategies aimed at improving bone health across future generations."
The study was funded by the charity Arthritis Research UK, with further funding support from the MRC, National Institute for Health Research (NIHR) and the Bupa Foundation.